The present invention relates to new taxoids of general formula (I) 
in which,
Z represents a hydrogen atom or a radical of general formula (II): 
xe2x80x83in which:
R1 represents
a benzoyl radical optionally substituted with one or more identical or different atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms and trifluoromethyl radicals,
a thenoyl or furoyl radical or
a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents:
an alkyl radical containing 1 to 8 carbon atoms,
an alkenyl radical containing 2 to 8 carbon atoms,
an alkynyl radical containing 3 to 8 carbon atoms,
a cycloalkyl radical containing 3 to 6 carbon atoms,
a cycloalkenyl radical containing 4 to 6 carbon atoms or
a bicycloalkyl radical containing 7 to 10 carbon atoms,
these radicals being optionally substituted with one or more substituents selected from halogen atoms, hydroxyl radicals, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, piperidino radicals, morpholino radicals, 1-piperazinyl radicals, said piperazinyl radicals being optionally substituted at position 4 with an alkyl radical containing 1 to 4 carbon atoms or with a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms, cycloalkyl radicals containing 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6 carbon atoms, phenyl radicals, said phenyl radicals being optionally substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4 carbon atoms, and alkoxy radicals containing 1 to 4 carbon atoms, cyano radicals, carboxyl radicals and alkoxycarbonyl radicals in which the alkyl portion contains 1 to 4 carbon atoms,
a phenyl or xcex1- or xcex2-naphthyl radical optionally substituted with one or more atoms or radicals selected from halogen atoms, alkyl radicals containing 1 to 4carbon atoms, and alkoxy radicals containing 1 to 4 carbon atoms,
a 5-membered aromatic heterocyclic radical preferably selected from furyl and thienyl radicals,
or a saturated heterocyclic radical containing 4 to 6 carbon atoms, optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms,
R3 represents
an unbranched or branched alkyl radical containing 1 to 8 carbon atoms,
an unbranched or branched alkenyl radical containing 2 to 8 carbon atoms,
an unbranched or branched alkynyl radical containing 2 to 8 carbon atoms,
a cycloalkyl radical containing 3 to 6 carbon atoms,
a phenyl or xcex1- or xcex2-naphthyl radical optionally substituted with one or more atoms or radicals selected from halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals,
or a 5-membered aromatic heterocycle containing one or more identical or different hetero atoms selected from nitrogen, oxygen and sulphur atoms and optionally substituted with one or more identical or different substituents selected from halogen atoms, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl and alkoxycarbonyl radicals,
with the understanding that, in the substituents of the phenyl, xcex1- or xcex2-naphthyl and aromatic heterocyclic radicals, the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms, and the aryl radicals are phenyl or xcex1- or xcex2-naphthyl radicals,
R4 represents
an alkoxy radical containing 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain,
an alkynyloxy radical containing 3 to 6 carbon atoms in an unbranched or branched chain,
a cycloalkyloxy radical containing 3 to 6 carbon atoms or
a cycloalkenyloxy radical containing 4 to 6 carbon atoms,
these radicals being optionally substituted with one or more substituents selected from halogen atoms, an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 1 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical, an N-alkylcarbamoyl radical and a N,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms, or both alkyl portions, together with the nitrogen atom to which they are linked, form a saturated 5- or 6-membered heterocyclic radical optionally containing a second hetero atom selected from; oxygen, sulphur and nitrogen atoms, said saturated 5- or 6-membered heterocyclic radical optionally being substituted with a substituent selected from an alkyl radical containing 1 to 4 carbon atoms, a phenyl radical, and a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms,
R5 represents
an alkoxy radical containing 1 to 6 carbon atoms in an unbranched or branched chain,
an alkenyloxy radical containing 3 to 6 carbon atoms,
an alkynyloxy radical containing 3 to 6 carbon atoms,
a cycloalkyloxy radical containing 3 to 6 carbon atoms or
a cycloalkenyloxy radical containing 3 to 6 carbon atoms, these radicals being optionally substituted with at least one substituent selected from halogen atoms, an alkoxy radical containing 1 to 4 carbon atoms, an alkylthio radical containing 2 to 4 carbon atoms, a carboxyl radical, an alkyloxycarbonyl radical in which the alkyl portion contains 1 to 4 carbon atoms, a cyano radical, a carbamoyl radical, an N-alkylcarbamoyl radical, and a N,N-dialkylcarbamoyl radical in which each alkyl portion contains 1 to 4 carbon atoms or, with the nitrogen atom to which it is linked, forms a saturated 5- or 6-membered heterocyclic radical optionally containing a second hetero atom selected from oxygen, sulphur and nitrogen atoms, optionally substituted with a substituent selected from an alkyl radical containing 1 to 4 carbon atoms, a phenyl radical and a phenylalkyl radical in which the alkyl portion contains 1 to 4 carbon atoms.
Preferably, the aryl radicals which can be represented by R3 are phenyl or xcex1- or xcex2-naphthyl radicals optionally substituted with one or more atoms or radicals selected from halogen atoms (fluorine, chlorine, bromine, iodine) alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, on the understanding that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or xcex1- or xcex2-naphthyl radicals.
Preferably, the heterocyclic radicals which can be represented by R3 are 5-membered aromatic heterocyclic radicals containing one or more identical or different atoms selected from nitrogen, oxygen and sulphur atoms, optionally substituted with one or more identical or different substituents selected from halogen atoms (fluorine, chlorine, bromine, iodine), alkyl radicals containing 1 to 4 carbon atoms, aryl radicals containing 6 or 10 carbon atoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy radicals containing 6 or 10 carbon atoms, amino radicals, alkylamino radicals containing 1 to 4 carbon atoms, dialkylamino radicals in which each alkyl portion contains 1 to 4 carbon atoms, acylamino radicals in which the acyl portion contains 1 to 4 carbon atoms, alkoxycarbonylamino radicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms, arylcarbonyl radicals in which the aryl portion contains 6 or 10 carbon atoms, cyano radicals, carboxyl radicals, carbamoyl radicals, alkylcarbamoyl radicals in which the alkyl portion contains 1 to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portion contains 1 to 4 carbon atoms, and alkoxycarbonyl radicals in which the alkoxy portion contains 1 to 4 carbon atoms.
Preferably, the radicals R4 and R5, which may be identical or different, represent unbranched or branched alkoxy radicals containing 1 to 6 carbon atoms, optionally substituted with a methoxy, ethoxy, ethylthio, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-pyrrolidinocarbonyl or N-piperidinocarbonyl radical.
More particularly, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents a tert-butyl radical and R3 represents an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl radical optionally substituted with one or more identical or different atoms or radicals selected from from halogen atoms (fluorine, chlorine), alkyl (methyl), alkoxy (methoxy), dialkylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (tert-butoxycarbonylamino), trifluoromethyl, a 2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a 3-thienyl radical, a 2-thiazolyl radical, a 4-thiazolyl radical, and a 5-thiazolyl radical, and R4 and R5, which may be identical or different, each represent an unbranched or branched alkoxy radical containing 1 to 6 carbon atoms.
Still more particularly, the present invention relates to the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) in which R1 represents a benzoyl radical or a radical R2xe2x80x94Oxe2x80x94COxe2x80x94 in which R2 represents a tert-butyl radical and R3 represents an isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl radical, and R4 and R5, which may be identical or different, each represent a methoxy, ethoxy or propoxy radical.
The products of general formula (I) in which Z represents a radical of general formula (II) display noteworthy antitumour and antileukaemic properties.
According to the present invention, the new products of general formula (I) in which Z represents a radical of general formula (II) may be obtained by esterification of a product of general formula (III): 
in which R4 and R5 are defined as above, by means of an acid of general formula (IV): 
in which R1 and R3 are defined as above, and either R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or R6 and R7 together form a saturated 5- or 6-membered heterocycle, or by means of a derivative of this acid, to obtain an ester of general formula (V): 
in which R1, R3, R4, R5, R6 and R7 are defined as above, followed by replacement of the protective groups represented by R7 and/or R6 and R7 by hydrogen atoms.
The esterification by means of an acid of general formula (IV) may be performed in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature from xe2x88x9210 to 90xc2x0 C.
The esterification may also be carried out using the acid of general formula (IV) in the form of the symmetrical anhydride, working in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of from 0 to 90xc2x0 C.
The esterification may also be carried out using the acid of general formula (IV) in halide form or in the form of a mixed anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (tertiary aliphatic amine), working in an organic solvent (ethers, esters, ketones, nitrites, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of from 0 to 80xc2x0 C.
Preferably, R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, or alternatively R6 and R7 together form a saturated 5- or 6-membered heterocycle.
When R6 represents a hydrogen atom, R7 preferably represents a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, xcex2-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyranyl radical.
When R6 and R7 together form a heterocycle, the latter is preferably an oxazolidine ring optionally monosubstituted or gem-disubstituted at position 2.
Replacement of the protective groups R7 and/or R6 and R7 by hydrogen atoms may be performed, depending on their nature, in the following manner:
1) when R6 represents a hydrogen atom and R7 represents a group protecting the hydroxyl function, replacement of the protective groups by hydrogen atoms is performed by means of an inorganic acid (hydrochloric acid, sulphuric acid, hydrofluoric acid) or organic acid (acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid) used alone or mixed, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitrites at a temperature of from xe2x88x9210 to 60xc2x0 C., or by means of a source of fluoride ions such as a hydrofluorine acid/triethylamine complex, or by catalytic hydrogenation,
2) when R6 and R7 together form a saturated 5- or 6-membered heterocycle, and more especially an oxazolidine ring of general formula (VI): 
in which R1 is defined as above and R6 and R9, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical in which the alkyl portion contains 1 to 4 carbon atoms and the aryl portion preferably represents a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical preferably representing a phenyl radical optionally substituted with one or more alkoxy radicals containing 1 to 4 carbon atoms, or alternatively R8 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical such as trichloromethyl or a phenyl radical substituted with a trihalomethyl radical such as trichloromethyl and R9 represents a hydrogen atom, or alternatively R8 and R9, together with the carbon atom to which they are linked, form a 4- to 7-membered ring, replacement of the protective group formed by R6 and R7 by hydrogen atoms may be performed, depending on the meanings of R1, R8 and R9, in the following manner:
a) when R1 represents a tert-butoxycarbonyl radical and R8 and R9, which may be identical or different, represent an alkyl radical or an aralkyl (benzyl) or aryl (phenyl) radical, or alternatively R6 represents a trihalomethyl radical or a phenyl radical substituted with a trihalomethyl radical and R9 represents a hydrogen atom, or alternatively R8 and R9 together form a 4- to 7-membered ring, treatment of the ester of general formula (V) with an inorganic or organic acid, where appropriate in an organic solvent such as an alcohol, yields the product of general formula (VII): 
in which R3, R4 and R5 are defined as above, which is acylated by means of benzoyl chloride in which the phenyl ring is optionally substituted or by means of thenoyl chloride, of furoyl chloride or of a product of general formula:
R2xe2x80x94Oxe2x80x94COxe2x80x94Xxe2x80x83xe2x80x83(VIII)
xe2x80x83in which R2 is defined as above and X represents a halogen atom (fluorine, chlorine) or a residue xe2x80x94Oxe2x80x94R2 or xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94R2, to obtain a product of general formula (I) in which Z represents a radical of general formula (II).
Preferably, the product of general formula (V) is treated with formic acid at a temperature in the region of 20xc2x0 C. to yield the product of general formula (VII).
Preferably, the acylation of the product of general formula (VII) by means of a benzoyl chloride in which the phenyl radical is optionally substituted or by means of thenoyl chloride, of furoyl chloride or of a product of general formula (VIII) is performed in an inert organic solvent chosen from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane, in the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction is performed at a temperature of from 0 to 50xc2x0 C., and preferably at about 20xc2x0 C.
b) when R1 represents an optionally substituted benzoyl radical, a thenoyl or furoyl radical or a radical R2Oxe2x80x94COxe2x80x94 in which R2 is defined as above, R8 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a phenyl radical substituted with one or more alkoxy radicals containing, 1 to 4 carbon atoms and R9 represents a hydrogen atom, replacement of the protective group formed by R6 and R7 by hydrogen atoms is performed in the presence of an inorganic acid (hydrochloric acid, sulphuric acid) or organic acid (acetic acid, methanesulphonic acid, trifluoromethanesulphonic acid, p-toluenesulphonic acid) used alone or mixed in a stoichiometric or catalytic amount, working in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature of from xe2x88x9210 to 60xc2x0 C., and preferably from 15 to 30xc2x0 C.
According to the invention, the products of general formula (III), that is to say the products of general formula (I) in which Z represents a hydrogen atom and R4 and R5 are defined as above, may be obtained from 10-deacetylbaccatin III of formula (IX): 
It can be especially advantageous to protect the hydroxyl functions at the positions 7 and 13 selectively, for example in the form of a silyl diether which may be obtained by the action of a silyl halide of general formula:
(R)3xe2x80x94Sixe2x80x94Halxe2x80x83xe2x80x83(X)
in which the symbols R, which may be identical or different, represent an alkyl radical containing 1 to 6 carbon atoms, optionally substituted with a phenyl radical, or a cycloalkyl radical containing 3 to 6 carbon atoms or a phenyl radical, on 10-deacetylbaccatin III, to obtain a product of general formula (XI): 
in which R is defined as above, followed by the action of a product of general formula:
Rxe2x80x24xe2x80x94X1xe2x80x83xe2x80x83(XII)
in which Rxe2x80x24 represents a radical such that Rxe2x80x24xe2x80x94O is identical to R4 defined as above and X1 represents a reactive ester residue such as a sulphuric or sulphonic ester residue or a halogen atom, to obtain a product of general formula (XIII): 
in which R and R4 are defined as above, the silyl protective groups of which are replaced by hydrogen atoms to obtain a product of general formula (XIV): 
in which R4 is defined as above, which is etherified selectively at position 7 by the action of a product of general formula:
Rxe2x80x25xe2x80x94X2xe2x80x83xe2x80x83(XV)
in which Rxe2x80x25 represents a radical such that Rxe2x80x25xe2x80x94O is identical to R5 defined as above and X2 represents a halogen atom or a reactive ester residue such as a sulphuric or sulphonic ester residue, to give the product of general formula (III).
Generally, the action of a silyl derivative of general formula (X) on 10-deacetylbaccatin III is performed in pyridine or triethylamine, where appropriate in the presence of an organic solvent such as an aromatic hydrocarbon, for instance benzene, toluene or xylenes, at a temperature between 0xc2x0 C. and the refluxing temperature of the reaction mixture.
Generally, the action of a product of general formula (XII) on a product of general formula (XI) is performed, after metalation of the hydroxyl function at position 10 by means of an alkali metal hydride, such as sodium hydride, an alkali metal amide, such as lithium amide, or an alkali metal alkylide, such as butyllithium, working in an organic solvent, such as dimnethylformamide or tetrahydrofuran, at a temperature of from 0 to 50xc2x0 C.
Generally, the replacement of the silyl protective groups of the product of general formula (XIII) by hydrogen atoms is performed by means of an acid such as hydrofluoric acid or trifluoroacetic acid in the presence of a base such as triethylamine or pyridine optionally substituted with one or more alkyl radicals containing 1 to 4 carbon atoms, the base optionally being combined with an inert organic solvent such as a nitrile, for instance acetonitrile, or a halogenated aliphatic hydrocarbon, such as dichloromethane, at a temperature of from 0 to 80xc2x0 C.
Generally, the action of a product of general formula (XV) on a product of general formula (XIV) is performed under the conditions described above for the action of a product of general formula (XII) on a product of general formula (XI).
According to the invention the products of general formula (I) in which Z represents a radical of general formula (II), R4 is defined as above and R5 is defined as above may be obtained from a product of general formula (XVI): 
in which R1, R3, R6 and R7 are defined as above, by silylation at position 7 by means of a product of general formula (X), to obtain a product of general formula (XVII): 
in which R, R1, R3, R6 and R7 are defined as above, which is functionalized at position 10 by means of a product of general formula (XII) to give a product of general formula (XVIII): 
in which R, R1, R3, R4, R6 and R7 are defined as above, the silyl protective group of which is replaced by a hydrogen atoms to give a product of general formula (XIX): 
which, by the action of a product of general formula (XV), yields the product of general formula (V), the protective groups of which are replaced by hydrogen atoms to give a product of general formula (I) in which Z represents a radical of general formula (II).
The reactions used for silylation, functionalization and replacement of the protective groups by hydrogen atoms are performed under conditions similar to those described above.
The products of general formula (XVI) may be obtained under the conditions described in European Patent EP 0,336,841 and international Applications PCT WO 92/09589 and WO 94/07878, the disclosures of which are hereby incorporated by reference in their entirety, or from the is products of general formula (XX): 
in which R1 and R3 are defined as above, according to known methods for protecting the hydroxyl function of the side chain without affecting the remainder of the molecule.
According to the invention, the products of general formula (I) in which Z represents a hydrogen atom or a radical of general formula (II) may be obtained by the action of activated Raney nickel, in the presence of an aliphatic alcohol containing 1 to 3 carbon atoms or an ether such as tetrahydrofuran or dioxane, on a product of general formula (XXI): 
in which R4 is defined as above and Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 6 carbon atoms, an alkenyl radical containing 2 to 6 carbon atoms, an alkynyl radical containing 2 to 6 carbon atoms, a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 3 to 6 carbon atoms, optionally substituted, or alternatively Rxe2x80x2 and Rxe2x80x3, together with the carbon atom to which they are linked, form a cycloalkyl radical containing 3 to 6 carbon atoms or a cycloalkenyl radical containing 4 to 6 carbon atoms, and Z1 represents a hydrogen atom or a radical of general formula (XXII): 
in which R1, R3, R6 and R7 are defined as above, and, to obtain a product of general formula (XXIII): 
followed, when Z1 represents a radical of general formula (XXII), that is to say when the product of general formula (XXIII) is identical to the product of general formula (V), by replacement of the protective groups represented by R6 and/or R6 and R7 by hydrogen atoms under the conditions described above.
Generally, the action of activated Raney nickel in the presence of an aliphatic alcohol or an ether is performed at a temperature of from xe2x88x9210 to 60xc2x0 C.
According to the invention, the product of general formula (XXI) in which Z1 and R4 are defined as above may be obtained by the action of a sulphoxide of general formula (XXIV): 
in which Rxe2x80x2 and Rxe2x80x3 are defined as above, on a product of general formula (XIX).
Generally, the reaction of the sulphoxide of general formula (XXIV), preferably dimethyl sulphoxide, with the product of general formula (XIX) is performed in the presence of a mixture of acetic acid and acetic anhydride or a derivative of acetic acid such as a haloacetic acid at a temperature of from 0xc2x0 to 50xc2x0 C., and preferably at about 25xc2x0 C.
The new products of general formula (I) obtained by carrying out the processes according to the invention may be purified according to known methods such as crystallization or chromatography.
The products of general formula (I) in which Z represents a radical of general formula (II) display noteworthy biological properties.
In vitro, measurement of the biological activity is performed on tubulin extracted from pig""s brain by the method of M. L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). Study of the depolymerization of microtubules to tubulin is performed according to the method of G. Chauvixc3xa8re et al., C. R. Acad. Sci., 29, series II, 501-503 (1981). In this study, the products of general formula (I) in which Z represents a radical of general formula (II) were shown to be at least as active as taxol and Taxotere.
In vivo, the products of general formula (I) in which Z represents a radical of general formula (II) were shown to be active in mice grafted with B16 melanoma at doses of from 1 to 30 mg/kg administered intraperitoneally, as well as on other liquid or solid tumours.
The new products have antitumour properties, and more especially activity against tumours which are resistant to Taxol(copyright) or to Taxotere(copyright). Such tumours comprise colon tumours which have a high expression of the mdr 1 gene (multiple drug resistance gene). Multiple drug resistance is a customary term relating to the resistance of a tumour to different products having different structures and mechanisms of action. Taxoids are generally known to be strongly recognized by experimental tumours such as P388/DOX, a cell line selected for its resistance to doxorubicin (DOX) which expresses mdr 1.